Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice
Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice
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二价金属转运蛋白 1 的整体过度表达可延缓青石棉诱导的雄性小鼠间皮癌发生
DOI：
10.1080/10715762.2018.1514604
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发表时间：
2018
影响因子：
3.3
通讯作者：
Toyokuni Shinya
中科院分区：
文献类型：
--
作者：
Funahashi Satomi;Okazaki Yasumasa;Nishiyama Takahiro;Ohyoshi Hidekazu;Yasui Hiroyuki;Nishida Kazuki;Matsui Shigeyuki;Toyokuni Shinya
暴露于石棉纤维是间皮癌发生的核心，其中间皮细胞内或附近的铁超载是一个关键的致病机制。另外，铁螯合治疗与去铁铁注射液或定期放血可以显著预防大鼠鳄鱼石诱导的间皮癌。然而，铁转运蛋白在石棉致癌过程中的作用仍然难以捉摸。在这里，我们研究了二价金属转运蛋白1 （DMT1; Slc11a2）的作用，它是一种铁（II）转运蛋白，不仅存在于十二指肠细胞的顶质膜上，也存在于每个细胞的溶酶体膜上，在鳄鱼石诱导的间皮癌中使用DMT1转基因（DMT1Tg）小鼠。DMT1Tg小鼠在正常饮食条件下表现出粘膜铁吸收阻滞，无癌易感性。我们意外地发现，dmt1tg小鼠的中性粒细胞和巨噬细胞在鳄鱼石的刺激下，超氧化物的产生都显著减少，并且在接触鳄鱼石1小时后，巨噬细胞表面显示出更高的铁含量。腹腔注射3mg鳄鱼石最终诱导约50%的野生型和dmt1tg小鼠发生恶性间皮瘤（分别为23/47和14/28）；该效应略微（p= 0.069）延迟了inDMT1Tg小鼠，促进了生存。硝基三乙酸的促进作用有限，inDMT1Tg小鼠和青绿石暴露后肝脏铁含量均显著升高。结果表明，globaldmt1过表达导致炎症细胞刺激后超氧化物生成减少，这可能延迟了鳄鱼石诱导的间皮癌的促进阶段。低耐力炎症细胞的DMT1Tg小鼠可能有助于评估炎症在各种病理中的参与。
Exposure to asbestos fiber is central to mesothelial carcinogenesis, for which iron overload in or near mesothelial cells is a key pathogenic mechanism. Alternatively, iron chelation therapy with deferasirox or regular phlebotomy was significantly preventive against crocidolite-induced mesothelial carcinogenesis in rats. However, the role of iron transporters during asbestos-induced carcinogenesis remains elusive. Here, we studied the role of divalent metal transporter 1 (DMT1; Slc11a2), which is a Fe(II) transporter, that is present not only on the apical plasma membrane of duodenal cells but also on the lysosomal membrane of every cell, in crocidolite-induced mesothelial carcinogenesis usingDMT1transgenic (DMT1Tg) mice.DMT1Tg mice show mucosal block of iron absorption without cancer susceptibility under normal diet. We unexpectedly found that superoxide production was significantly decreased upon stimulation with crocidolite both in neutrophils and macrophages ofDMT1Tg mice, and the macrophage surface revealed higher iron content 1 h after contact with crocidolite. Intraperitoneal injection of 3 mg crocidolite ultimately induced malignant mesothelioma in ∼50% of bothwild-typeandDMT1Tg mice (23/47 and 14/28, respectively); this effect was marginally (p= 0.069) delayed inDMT1Tg mice, promoting survival. The promotional effect of nitrilotriacetic acid was limited, and the liver showed significantly higher iron content both inDMT1Tg mice and after crocidolite exposure. The results indicate that globalDMT1overexpression causes decreased superoxide generation upon stimulation in inflammatory cells, which presumably delayed the promotional stage of crocidolite-induced mesothelial carcinogenesis.DMT1Tg mice with low-stamina inflammatory cells may be helpful to evaluate the involvement of inflammation in various pathologies.